Phase 1b/2 Study of Oral NB-4746 with Standard Riluzole in Participants with Amyotrophic Lateral Sclerosis: Safety and Tolerability Assessment

Primary objective: to evaluate the safety profile of oral NB‑4746 over 28 days in participants with Amyotrophic Lateral Sclerosis (ALS) during the Phase 1b segment, and to continue safety assessment in the Phase 2 and open‑label extension cohorts. This objective addresses the essential need to characterize tolerability and adverse event incidence in a disease with limited therapeutic options, informing risk–benefit considerations for further development.

Secondary objectives:

• Phase II: to determine the effect of NB‑4746 on neurofilament light chain (NfL) concentrations, providing a pharmacodynamic marker of neuronal injury.
• Open‑label extension: to evaluate longitudinal changes in NfL concentrations during continued NB‑4746 exposure.

Thirty‑four participants were enrolled, comprising both male and female adults aged 18 to 80 years. All subjects had a confirmed diagnosis of Amyotrophic Lateral Sclerosis according to the Gold Coast Criteria and met disease‑duration requirements (symptom onset ≤48 months for the Phase 1b cohort and ≤24 months for the Phase 2 cohort). Inclusion required a score of at least 2 on the swallowing domain of the ALSFRS‑R, a slow vital capacity of ≥60 % of predicted, and stable dosing of riluzole (≥60 days) or completion of at least one edaravone cycle prior to screening. Participants were required to be able to provide informed consent and to comply with contraceptive requirements during the study. Screening laboratory values had to be within normal limits. The cohort represented patients with ALS in generally stable health, without additional exclusion criteria specified in the source.

The study is a Phase 1b/2 randomized, double-blind, placebo-controlled trial evaluating oral NB‑4746 in participants with Amyotrophic Lateral Sclerosis (ALS). After an initial screening visit to confirm eligibility (Gold Coast ALS criteria, symptom onset ≤48 months for Phase 1b or ≤24 months for Phase 2, age 18‑80, SVC ≥60 % predicted, stable riluzole dose ≥60 days, and required laboratory values), eligible subjects are randomized on Day 1 to receive NB‑4746, NB‑4746 plus riluzole, or matching placebo capsules. In Phase 1b the treatment period lasts 28 days with safety assessments at Days 7, 14, and 28; Phase 2 extends treatment with regular follow‑up visits (e.g., monthly) until an end‑of‑study visit scheduled after the final treatment cycle, all within the overall trial window of June 2026 to December 2027. Primary safety endpoints comprise the number of treatment‑emergent adverse events, serious adverse events, and changes in vital signs, laboratory tests, and 12‑lead ECGs. Participant involvement spans the assigned treatment phase plus a follow‑up period, ranging from 28 days in Phase 1b to several months in Phase 2 and the open‑label extension. Early termination may occur for serious adverse events, major protocol violations, withdrawal of consent, or the need for prohibited concomitant therapy.

The investigational product NB-4746 is supplied as oral capsules. The formulation contains the active substance nb‑4746 and is administered by the oral route. Specific dose strength and frequency of administration are defined in the study protocol and are consistent with the 28‑day safety assessment period in Phase 1b and the extended safety evaluation in Phase 2 and the open‑label extension.

The study includes oral capsules of Riluzole as a concomitant therapy. Each capsule contains the active substance riluzole and is taken by the oral route. Dosing details, including amount and schedule, follow the standard prescribing information and are incorporated into the trial regimen as required.

A matching placebo is provided as oral capsules labeled “Placebo capsules for NB 4746.” The placebo capsules are identical in appearance to the active NB‑4746 capsules and are administered orally according to the same schedule as the investigational product to maintain blinding.